Synthesis of scabronines and analogues thereof
View Patent ↗A novel synthesis of scabronines, which are related to a broader class of angularly fused tricyclic diterpenoids known as cyathanes, is provided. Scabronine G, its methyl ester derivative, and other analogs have been shown to have neurotrophic activity. Therefore, these compounds are particularly useful in treating neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's diseases, etc. The invention provides for the synthesis of scabronines as well as analogs thereof. Pharmaceutical compositions and method of using the inventive compounds are also provided.
1. A compound of the formula
wherein
each dashed line independently represents the absence of a bond or a carbon-carbon bond of a carbon-carbon double bond;
m is an integer between 0 and 3, inclusive;
n is an integer between 0 and 2, inclusive;
R is C(═O)R 1 or CN; wherein
R 1 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR A ; —OH; —C(═O)R A ; —CO 2 R A ; —CN; —SCN; —SR A ; —SH; —N(R A ) 2 ; —NHR A ; —NH 2 ; or —C(R A ) 3 ; wherein each occurrence of R A is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety;
R 2 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR B ; —OH; —C(═O)R B ; —CO 2 R B ; —CN; —SCN; —SR B ; —SH; —SOR B ; —SO 2 R B ; —NO 2 ; —N(R B ) 2 ; —NHR B ; —NH 2 ; —NHC(═O)R B ; —OC(═O)R B ; or —C(R B ) 3 ; wherein each occurrence of R B is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety;
R 3 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR C ; —OH; —C(═O)R C ; —CO 2 R C ; —CN; —SCN; —SR C ; —SH; —SOR C ; —SO 2 R C ; —NO 2 ; —N(R C ) 2 ; —NHR C ; —NH 2 ; —NHC(═O)R C ; —OC(═O)R C ; or —C(R C ) 3 ; wherein each occurrence of R C is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety;
R 4 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR D ; —OH; —C(═O)R D ; —CO 2 R D ; —CN; —SCN; —SR D ; —SH; —SOR D ; —SO 2 R D ; —NO 2 ; —N(R D ) 2 ; —NHR D ; —NH 2 ; —NHC(═O)R D ; —OC(═O)R D ; or —C(R D ) 3 ; wherein each occurrence of R D is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety;
R 5 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR E ; —OH; —C(═O)R E ; —CO 2 R E ; —CN; —SCN; —SR E ; —SH; —SOR E ; —SO 2 R E ; —NO 2 ; —N(R E ) 2 ; —NHR E ; —NH 2 ; —NHC(═O)R E ; —OC(═O)R E ; or —C(R E ) 3 ; wherein each occurrence of R E is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety;
R 6 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR F ; —OH; —C(═O)R F ; —CO 2 R F ; —CN; —SCN; —SR F ; —SH; —SOR F ; —SO 2 R F ; —NO 2 ; —N(R F ) 2 ; —NHR F ; —NH 2 ; —NHC(═O)R F ; —OC(═O)R F ; or —C(R F ) 3 ; wherein each occurrence of R F is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety;
R 5 and R 6 may be take together to form ═O, ═S, ═NR E , ═C(R E ) 2 , or a carbocyclic or heterocyclic moiety; or a therapeutically acceptable salt thereof;
wherein at least one of m and n is 1.
2. The compound of claim 1 of formula:
3. The compound of claim 1 of formula:
4. The compound of claim 1 of formula:
5. The compound of claim 1 of formula:
6. The compound of claim 1 of formula:
7. The compound of claim 1 of formula:
8. The compound of claim 1 of formula:
9. The compound of claim 1 of formula:
10. The compound of claim 1 of any one of the formulae:
11. The compound of claim 1 , having the formula:
12. The compound of claim 1 of any one of the formulae:
13. The compound of claim 1 of one of the formulae:
14. The compound of claim 1 , wherein m is 1.
15. The compound of claim 1 , wherein m is 2.
16. The compound of claim 1 , wherein m is 0.
17. The compound of claim 1 , wherein n is 1.
18. The compound of claim 1 , wherein n is 2.
19. The compound of claim 1 , wherein n is 0.
20. The compound of claim 1 , wherein m and n are both 1.
21. The compound of claim 1 , wherein R is C(═O)R 1 .
22. The compound of claim 21 , wherein R 1 is hydrogen.
23. The compound of claim 21 , wherein R 1 is —OR A .
24. The compound of claim 21 , wherein R 1 is —OH.
25. The compound of claim 21 , wherein R 1 is —OR A , wherein R A is C 1 -C 6 alkyl.
26. The compound of claim 21 , wherein R 1 is —OMe.
27. The compound of claim 21 , wherein R 1 is —N(R A ) 2 .
28. The compound of claim 1 , wherein R 2 is hydrogen.
29. The compound of claim 1 , wherein R 2 is C 1 -C 6 alkyl.
30. The compound of claim 1 , wherein R 2 is methyl.
31. The compound of claim 1 , wherein R 3 is hydrogen.
32. The compound of claim 1 , wherein R 3 is C 1 -C 6 alkyl.
33. The compound of claim 1 , wherein R 3 is —CHO.
34. The compound of claim 1 , wherein R 3 is acyl.
35. The compound of claim 1 , wherein R 3 is —CH 2 OR C .
36. The compound of claim 1 , wherein R 3 is —CH 2 OR C , wherein R C is hydrogen, C 1 -C 6 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
37. The compound of claim 1 , wherein R 3 is —CH 2 OH.
38. The compound of claim 1 , wherein R 4 is hydrogen.
39. The compound of claim 1 , wherein R 4 is C 1 -C 6 alkyl.
40. The compound of claim 1 , wherein R 4 is methyl.
41. The compound of claim 1 , wherein R 4 is ethyl.
42. The compound of claim 1 , wherein R 4 is propyl.
43. The compound of claim 1 , wherein R 4 is iso-propyl.
44. The compound of claim 1 , wherein R 4 is substituted or unsubstituted aryl.
45. The compound of claim 1 , wherein R 4 is substituted or unsubstituted heteroaryl.
46. The compound of claim 1 , wherein R 4 is acyl.
47. The compound of claim 1 , wherein R 5 is hydrogen.
48. The compound of claim 1 , wherein R 5 is —OR E .
49. The compound of claim 1 , wherein R 5 is —OH.
50. The compound of claim 1 , wherein R 6 is hydrogen.
51. The compound of claim 1 , wherein R 6 is —OR F .
52. The compound of claim 1 , wherein R 6 is —OH.
53. The compound of claim 1 , wherein R 5 is —OH; and R 6 is hydrogen.
54. The compound of claim 1 , wherein R 5 is hydrogen; and R 6 is —OH.
55. The compound of claim 1 , wherein R 5 and R 6 are taken together to be ═O.
56. The compound of claim 1 , wherein R 5 and R 6 are taken together to be ═S.
57. The compound of claim 1 , wherein R 5 and R 6 are taken together to be ═C(R E ) 2 .
58. The compound of claim 1 , wherein R 5 and R 6 are taken together to be ═NR E .
59. The compound of claim 1 , wherein R 5 and R 6 are taken together to be a carbocyclic or heterocyclic moiety optionally substituted.
60. The compound of claim 1 of one of the formulae:
61. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.